Review of embryo-fetal developmental toxicity studies performed for pharmaceuticals approved by FDA in 2022 and 2023

Abstract

92 novel drugs were approved by the FDA in 2022–2023. 48 of these approvals were for orphan indications. Embryofetal development (EFD) studies were conducted for 79 % of approvals. Rats and rabbits were the most common species used (77 % and 62 % of studies, respectively). For the testing of biopharmaceuticals, rodents were more often used (43 % of EFD studies) than non-human primates (29 %) and rabbits (29 %). Most (75 %) biopharmaceuticals intended to treat cancer were approved without EFD studies. Amongst the 41 drugs for which both rat and rabbit EFD studies were performed, the rabbit appeared more sensitive to both maternal toxicity and developmental toxicity (61 % and 63 % of drugs, respectively). Most drugs (76 %) showed more than a 2-fold difference in the LOAEL for developmental toxicity between the rat and rabbit. EFD studies were not required for drugs with a mode of action known to pose a clear hazard for pregnancy and further EFD studies were generally not performed when clinically relevant developmental effects had already been observed in one species or in a preliminary EFD study. Many drug labels showed minor deviations from the PLLR rule: the metric used to calculate exposure margins and the presence or absence of maternal toxicity were not always specified. These omissions, however, are of little significance for the prescriber. The five reviews in this series now show compiled information on EFD studies for all small molecule pharmaceuticals approved since 2014 and for all therapeutic monoclonal antibodies approved to date.